MAMILNet: advancing precision oncology with multi-scale attentional multi-instance learning for whole slide image analysis.

Background: Whole Slide Image (WSI) analysis, driven by deep learning algorithms, has the potential to revolutionize tumor detection, classification, and treatment response prediction. However, challenges persist, such as limited model generalizability across various cancer types, the labor-intensive nature of patch-level annotation, and the necessity of integrating multi-magnification information to attain a comprehensive understanding of pathological patterns. Methods: In response to these challenges, we introduce MAMILNet, an innovative multi-scale attentional multi-instance learning framework for WSI analysis. The incorporation of attention mechanisms into MAMILNet contributes to its exceptional generalizability across diverse cancer types and prediction tasks. This model considers whole slides as "bags" and individual patches as "instances." By adopting this approach, MAMILNet effectively eliminates the requirement for intricate patch-level labeling, significantly reducing the manual workload for pathologists. To enhance prediction accuracy, the model employs a multi-scale "consultation" strategy, facilitating the aggregation of test outcomes from various magnifications. Results: Our assessment of MAMILNet encompasses 1171 cases encompassing a wide range of cancer types, showcasing its effectiveness in predicting complex tasks. Remarkably, MAMILNet achieved impressive results in distinct domains: for breast cancer tumor detection, the Area Under the Curve (AUC) was 0.8872, with an Accuracy of 0.8760. In the realm of lung cancer typing diagnosis, it achieved an AUC of 0.9551 and an Accuracy of 0.9095. Furthermore, in predicting drug therapy responses for ovarian cancer, MAMILNet achieved an AUC of 0.7358 and an Accuracy of 0.7341. Conclusion: The outcomes of this study underscore the potential of MAMILNet in driving the advancement of precision medicine and individualized treatment planning within the field of oncology. By effectively addressing challenges related to model generalization, annotation workload, and multi-magnification integration, MAMILNet shows promise in enhancing healthcare outcomes for cancer patients. The framework's success in accurately detecting breast tumors, diagnosing lung cancer types, and predicting ovarian cancer therapy responses highlights its significant contribution to the field and paves the way for improved patient care.

Habitat Radiomics Based on MRI for Predicting Platinum Resistance in Patients with High-Grade Serous Ovarian Carcinoma: A Multicenter Study.

RATIONALE AND OBJECTIVES: This study aims to explore the feasibility of MRI-based habitat radiomics for predicting response of platinum-based chemotherapy in patients with high-grade serous ovarian carcinoma (HGSOC), and compared to conventional radiomics and deep learning models. MATERIALS AND METHODS: A retrospective study was conducted on HGSOC patients from three hospitals. K-means algorithm was used to perform clustering on T2-weighted images (T2WI), contrast-enhanced T1-weighted images (CE-T1WI), and apparent diffusion coefficient (ADC) maps. After feature extraction and selection, the radiomics model, habitat model, and deep learning model were constructed respectively to identify platinum-resistant and platinum-sensitive patients. A nomogram was developed by integrating the optimal model and clinical independent predictors. The model performance and benefit was assessed using the area under the receiver operating characteristic curve (AUC), net reclassification index (NRI), and integrated discrimination improvement (IDI). RESULTS: A total of 394 eligible patients were incorporated. Three habitats were clustered, a significant difference in habitat 2 (weak enhancement, high ADC values, and moderate T2WI signal) was found between the platinum-resistant and platinum-sensitive groups (P < 0.05). Compared to the radiomics model (0.640) and deep learning model (0.603), the habitat model had a higher AUC (0.710). The nomogram, combining habitat signatures with a clinical independent predictor (neoadjuvant chemotherapy), yielded a highest AUC (0.721) among four models, with positive NRI and IDI. CONCLUSION: MRI-based habitat radiomics had the potential to predict response of platinum-based chemotherapy in patients with HGSOC. The nomogram combining with habitat signature had a best performance and good model gains for identifying platinum-resistant patients.

Irreversible repolarization of tumour-associated macrophages by low-Pi stress inhibits the progression of hepatocellular carcinoma.

Numerous studies have shown the positive correlation between high levels of Pi and tumour progression. A critical goal of macrophage-based cancer therapeutics is to reduce anti-inflammatory macrophages (M2) and increase proinflammatory antitumour macrophages (M1). This study aimed to investigate the relationship between macrophage polarization and low-Pi stress. First, the spatial populations of M2 and M1 macrophages in 22 HCC patient specimens were quantified and correlated with the local Pi concentration. The levels of M2 and M1 macrophage markers expressed in the peritumour area were higher than the intratumour levels, and the expression of M2 markers was positively correlated with Pi concentration. Next, monocytes differentiated from THP-1 cells were polarized against different Pi concentrations to investigate the activation or silencing of the expression of p65, IκB-α and STAT3 as well as their phosphorylation. Results showed that low-Pi stress irreversibly repolarizes tumour-associated macrophages (TAMs) towards the M1 phenotype by silencing stat6 and activating p65. Moreover, HepG-2 and SMCC-7721 cells were cultured in conditioned medium to investigate the innate anticancer immune effects on tumour progression. Both cancer cell lines showed reduced proliferation, migration and invasion, as epithelial-mesenchymal transition (EMT) was inactivated. In vivo therapeutic effect on the innate and adaptive immune processes was validated in a subcutaneous liver cancer model by the intratumoural injection of sevelamer. Tumour growth was significantly inhibited by the partial deprivation of intratumoural Pi as the tumour microenvironment under low-Pi stress is more immunostimulatory. The anticancer immune response, activated by low-Pi stress, suggests a new macrophage-based immunotherapeutic modality.

Low Pi stress enhances the sensitivity of hepatocellular carcinoma to sorafenib.

Sorafenib is a tyrosine kinase inhibitor for the treatment of advanced-stage HCC; however, clinical trials of sorafenib failed to demonstrate long-term survival benefits due to drug resistance. Low Pi stress has been shown to inhibit tumor growth and the expression of multidrug resistance-associated proteins. In this study, we investigated the sensitivity of HCC to sorafenib under conditions of low Pi stress. As a result, we found that low Pi stress facilitated sorafenib-mediated suppression of migration and invasion of HepG-2 and Hepa1-6 cells by decreasing the phosphorylation or expression of AKT, Erk and MMP-9. Angiogenesis was inhibited due to decreased expression of PDGFR under low Pi stress. Low Pi stress also decreased the viability of sorafenib-resistant cells by directly regulating the expression of AKT, HIF-1a and P62. In vivo drug sensitivity analysis in the four animal models showed a similar tendency that low Pi stress enhances sorafenib sensitivity in both the normal and drug-resistant models. Altogether, low Pi stress enhances the sensitivity of hepatocellular carcinoma to sorafenib and expands the indications for sevelamer.

Development and validation of MRI-based radiomics model to predict recurrence risk in patients with endometrial cancer: a multicenter study.

OBJECTIVES: To develop a fusion model based on clinicopathological factors and MRI radiomics features for the prediction of recurrence risk in patients with endometrial cancer (EC). METHODS: A total of 421 patients with histopathologically proved EC (101 recurrence vs. 320 non-recurrence EC) from four medical centers were included in this retrospective study, and were divided into the training (n = 235), internal validation (n = 102), and external validation (n = 84) cohorts. In total, 1702 radiomics features were respectively extracted from areas with different extensions for each patient. The extreme gradient boosting (XGBoost) classifier was applied to establish the clinicopathological model (CM), radiomics model (RM), and fusion model (FM). The performance of the established models was assessed by the discrimination, calibration, and clinical utility. Kaplan-Meier analysis was conducted to further determine the prognostic value of the models by evaluating the differences in recurrence-free survival (RFS) between the high- and low-risk patients of recurrence. RESULTS: The FMs showed better performance compared with the models based on clinicopathological or radiomics features alone but with a reduced tendency when the peritumoral area (PA) was extended. The FM based on intratumoral area (IA) [FM (IA)] had the optimal performance in predicting the recurrence risk in terms of the ROC, calibration curve, and decision curve analysis. Kaplan-Meier survival curves showed that high-risk patients of recurrence defined by FM (IA) had a worse RFS than low-risk ones of recurrence. CONCLUSIONS: The FM integrating intratumoral radiomics features and clinicopathological factors could be a valuable predictor for the recurrence risk of EC patients. CLINICAL RELEVANCE STATEMENT: An accurate prediction based on our developed FM (IA) for the recurrence risk of EC could facilitate making an individualized therapeutic decision and help avoid under- or over-treatment, therefore improving the prognosis of patients. KEY POINTS: • The fusion model combined clinicopathological factors and radiomics features exhibits the highest performance compared with the clinicopathological model and radiomics model. • Although higher values of area under the curve were observed for all fusion models, the performance tended to decrease with the extension of the peritumoral region. • Identifying patients with different risks of recurrence, the developed models can be used to facilitate individualized management.

Development and Validation of an MRI-based Radiomics Nomogram for Assessing Deep Myometrial Invasion in Early Stage Endometrial Adenocarcinoma.

RATIONALE AND OBJECTIVES: To establish a radiomics nomogram for detecting deep myometrial invasion (DMI) in early stage endometrioid adenocarcinoma (EAC). MATERIALS AND METHODS: A total of 266 patients with stage I EAC were divided into training (n = 185) and test groups (n = 81). Logistic regression were used to identify clinical predictors. Radiomics features were extracted and selected from multiparameter MR images. The important clinical factors and radiomics features were integrated into a nomogram. A receiver operating characteristic curve was used to evaluate the nomogram. Two radiologists evaluated MR images with or without the help of the nomogram to detect DMI. The clinical benefit of using the nomogram was evaluated by decision curve analysis (DCA) and by calculating net reclassification index (NRI) and integrated discrimination index (IDI). RESULTS: Age and CA125 were independent clinical predictors. The area under the curves of the clinical parameters, radiomics signature and nomogram in evaluating DMI were 0.744, 0.869 and 0.883, respectively. The accuracies of the two radiologists increased from 79.0% and 80.2% to 90.1% and 92.5% when they used the nomogram. The NRI of the two radiologists were 0.262 and 0.318, and the IDI were 0.322 and 0.405. According to DCA, the nomogram showed a higher net benefit than the radiomics signature or unaided radiologists. Cross-validation showed the outcome of radiomics analysis may not be influenced by changes in field strength. CONCLUSION: The radiomics nomogram based on radiomics features and clinical factors can help radiologists evaluate DMI and improve their accuracy in predicting DMI in early stage EAC.

Evaluation of the safety and efficacy of transarterial sevelamer embolization in a rabbit liver cancer model: A challenge on the size rule for vascular occlusion.

As the most efficient method to treat hepatocellular carcinoma in the immediate or advanced stage, transarterial chemoembolization (TACE) is coming into the era of microsphere (MP). Drug-eluting beads have shown their huge potential as an embolic agent and drug carrier for chemoembolization, but their sizes are strictly limited to be above 40 µm, which was considered to occlude vessels in a safe mode. microsphere smaller than 40 µm is easy to be washed out and transported to the normal liver lobe or other organs, causing severe adverse events and failed embolization. To determine whether sevelamer ultrafine particle (0.2-0.5 µm) is qualified as a safe and efficient embolic agent, we investigated the safety and therapeutic efficiency of transarterial sevelamer embolization (TASE) in the VX2 rabbit liver cancer model, aiming to challenge the "40 µm" rule on the selection criteria of the MP. In a four-arm study, blank bead (Callisphere, 100-300 µm), luminescent polystyrene microsphere (10, 100 µm), and sevelamer particle were transarterially administered to evaluate the threshold size of the MP size for intrahepatic or extrahepatic permeability. Another four-arm study was designed to clarify the safety and efficiency of preclinical transarterial sevelamer embolizationTASE tests over other techniques. Sham (saline), TASE, C-TACE, and D-TACE (n = 6) were compared in terms of serum chemistry, histopathology, and tumor necrosis ratio. In the first trials, the "40 µm" rule was detectable on the VX2 cancer model, but the regulation has no application to the new embolic agent as sevelamer ultrafine particles have not been found to leak out from the VX2 lesions, only found in the embolized vessels. Pathology proves that less viable tumor residue was found 2 weeks after the procedure, evidencing a better therapeutic outcome. No adverse events were found except for a short stress response. These results indicate that sevelamer is a safe and efficient embolic as an alternative to the current MP-based embolization therapy techniques.

Different multiparametric MRI-based radiomics models for differentiating stage IA endometrial cancer from benign endometrial lesions: A multicenter study.

Purpose: The aim of this study was to evaluate the value of different multiparametric MRI-based radiomics models in differentiating stage IA endometrial cancer (EC) from benign endometrial lesions. Methods: The data of patients with endometrial lesions from two centers were collected. The radiomics features were extracted from T2-weighted imaging (T2WI), diffusion-weighted imaging (DWI), apparent diffusion coefficient (ADC) map, and late contrast-enhanced T1-weighted imaging (LCE-T1WI). After data dimension reduction and feature selection, nine machine learning algorithms were conducted to determine which was the optimal radiomics model for differential diagnosis. The univariate analyses and logistic regression (LR) were performed to reduce valueless clinical parameters and to develop the clinical model. A nomogram using the radscores combined with clinical parameters was developed. Two integrated models were obtained respectively by the ensemble strategy and stacking algorithm based on the clinical model and optimal radiomics model. The area under the curve (AUC), clinical decisive curve (CDC), net reclassification index (NRI), and integrated discrimination index (IDI) were used to evaluate the performance and clinical benefits of the models. Results: A total of 371 patients were incorporated. The LR model was the optimal radiomics model with the highest average AUC (0.854) and accuracy (0.802) in the internal and external validation groups (AUC = 0.910 and 0.798, respectively), and outperformed the clinical model (AUC = 0.739 and 0.592, respectively) or the radiologist (AUC = 0.768 and 0.628, respectively). The nomogram (AUC = 0.917 and 0.802, respectively) achieved better discrimination performance than the optimal radiomics model in two validation groups. The stacking model (AUC = 0.915) and ensemble model (AUC = 0.918) had a similar performance compared with the nomogram in the internal validation group, whereas the AUCs of the stacking model (AUC = 0.792) and ensemble model (AUC = 0.794) were lower than those of the nomogram and radiomics model in the external validation group. According to the CDC, NRI, and IDI, the optimal radiomics model, nomogram, stacking model, and ensemble model achieved good net benefits. Conclusions: Multiparametric MRI-based radiomics models can non-invasively differentiate stage IA EC from benign endometrial lesions, and LR is the best machine learning algorithm. The nomogram presents excellent and stable diagnostic efficiency.

Exosomes Derived from Glioma Cells under Hypoxia Promote Angiogenesis through Up-regulated Exosomal Connexin 43.

Glioblastoma multiform (GBM) is a highly aggressive primary brain tumor. Exosomes derived from glioma cells under a hypoxic microenvironment play an important role in tumor biology including metastasis, angiogenesis and chemoresistance. However, the underlying mechanisms remain to be elucidated. In this study, we aimed to explore the role of connexin 43 on exosomal uptake and angiogenesis in glioma under hypoxia. U251 cells were exposed to 3% oxygen to achieve hypoxia, and the expression levels of HIF-1α and Cx43, involved in the colony formation and proliferation of cells were assessed. Exosomes were isolated by differential velocity centrifugation from U251 cells under normoxia and hypoxia (Nor-Exos and Hypo-Exos), respectively. Immunofluorescence staining, along with assays for CCK-8, tube formation and wound healing along with a transwell assay were conducted to profile exosomal uptake, proliferation, tube formation, migration and invasion of HUVECs, respectively. Our results revealed that Hypoxia significantly up-regulated the expression of HIF-1α in U251 cells as well as promoting proliferation and colony number. Hypoxia also increased the level of Cx43 in U251 cells and in the exosomes secreted. The uptake of Dio-stained Hypo-Exos by HUVECs was greater than that of Nor-Exos, and inhibition of Cx43 by 37,43gap27 or lenti-Cx43-shRNA efficiently prevented the uptake of Hypo-Exos by recipient endothelial cells. In addition, the proliferation and total loops of HUVECs were remarkably increased at 24 h, 48 h, and 10 h after Hypo-Exos, respectively. Notably, 37,43gap27, a specific Cx-mimetic peptide blocker of Cx37 and Cx43, efficiently alleviated Hypo-Exos-induced proliferation and tube formation by HUVECs. Finally, 37,43gap27 also significantly attenuated Hypo-Exos-induced migration and invasion of HUVECs. These findings demonstrate that exosomal Cx43 contributes to glioma angiogenesis mediated by Hypo-Exos, and suggests that exosomal Cx43 might serve as a potential therapeutic target for glioblastoma.

Preliminary Application of Magnetization Transfer Imaging in the Study of Normal Uterus and Uterine Lesions.

Purpose: The aim of this study is to evaluate the utility of magnetization transfer (MT) imaging in the study of normal uterus and common uterine lesions. Methods: This prospective study enrolled 160 consecutive patients with suspected uterine lesions. MT ratio (MTR) map was obtained by pelvic MT imaging on a 3.0T MRI scanner. Patients confirmed by pathology were divided into microscopic lesion group and lesion group, according to whether the maximum diameter of the lesion was less than 5 mm. After evaluating and eliminating patients with poor image quality by a three-point Likert scale, MTR values of lesions and normal endometrium, myometrium, and cervix were independently measured on the MTR map by two radiologists. Inter-reader agreement was evaluated. MTR values were compared among different uterine lesions and normal uterine structures using the Mann-Whitney U test with Bonferroni correction. Receiver operating characteristic curve was performed. The correlations between age and MTR values were explored by Pearson correlation analyses. Results: A total of 96 patients with 121 uterine lesions in the lesion group and 41 patients in the microscopic lesion group were measured. The MTR values among normal endometrium, myometrium, and cervix were statistical significant differences (P < 0.05). There were significant differences between endometrial cancer and normal endometrium and between cervical cancer and normal cervix (both P ≤ 0.001). Area under the curve (AUC) for diagnosing endometrial and cervical cancer were 0.73 and 0.86. Myometrial lesions had significantly higher MTR values than endometrial lesions and cervical cancer (both P < 0.001), and the AUC for differentiating myometrial lesions from them were 0.89 and 0.94. MTR values of endometrial cancer were significantly higher than those of cervical cancer (P = 0.02). There was a critical correlation between age and MTR values in endometrial cancer (r = 0.81, P = 0.04). Conclusions: MTR values showed significant differences among normal uterine structures. It was valuable for diagnosing and differentiating uterine cancer. MTR values could differentiate myometrial lesions from endometrial or cervical lesions.

Sevelamer arsenite nanoparticle as a Pi-responsive drug carrier and embolic agent for chemoembolization.

Arsenic trioxide (As2O3, ATO) has limited therapeutic benefit to treat solid tumors, whether used alone or in combination. Nanoscale drug delivery vehicles have great potential to overcome the limitation of the utility of ATO by rapid renal clearance and dose-limiting toxicity. Polymeric materials ranging from gelatin foam to synthetic polymers such as poly(vinyl alcohol) were developed for vascular embolic or chemoembolic applications. Recently, we have introduced sevelamer, an oral phosphate binder, as a new polymeric embolic for vascular interventional therapy. In this paper, sevelamer arsenite nanoparticle with a polygonal shape and a size of 50-300 nm, synthesized by anionic exchange from sevelamer chloride, was developed as a Pi-responsive bifunctional drug carrier and embolic agent for chemoembolization therapy. At the same arsenic dosage, sevelamer arsenite-induced severer tumor necrosis than ATO on the VX2 cancer model. In vitro tests evidenced that Pi deprivation by sevelamer could enhance ATO's anticancer effect. The results showed that ATO in Pi starvation reduced cell viability, induced more apoptosis, and diminished the mitochondrial membrane potential (Δψm) of cells since Pi starvation helps ATO to further down-regulate Bcl-2 expression, up-regulate Bax expression, enhance the activation of caspase-3 and increase the release of cytochrome c, and the production of excessive reactive oxygen species (ROS). Sevelamer arsenite not only plays a Pi-activated nano-drug delivery system but also integrated anticancer drug with embolic for interventional therapy. Therefore, our results presented a new administration route of ATO as well as an alternative chemoembolization therapy.

Pi-inducedin-situaggregation of sevelamer nanoparticles for vascular embolization.

Decades have witnessed rapid progress of polymeric materials for vascular embolic or chemoembolic applications. Commercially available polymeric embolics range from gelatin foam to synthetic polymers such as poly(vinyl alcohol). Current systems under investigation include tunable, bioresorbable microspheres composed of chitosan or poly(ethylene glycol) derivatives,in situgelling liquid embolics with improved safety profiles, and radiopaque embolics that are trackablein vivo. In this paper, we proposed a concept of 'responsive embolization'. Sevelamer, clinically proved as an inorganic phosphate binder, was ground into nanoparticles. Sevelamer nanoparticle is highly mobile and capable of swelling and aggregating in the presence of endogenous inorganic phosphate, thereby effectively occluding blood flow in the vessel as it was administered as an embolic agent for interventional therapy. Moreover, citrated sevelamer nanoparticles delayed the aggregation, preferable to penetrate deeply into the capillary system. On the rabbit VX2 liver cancer model, both sevelamer particles aggregates occlude the tumor feeding artery, but backflow was found for the pristine one, thereby citrate passivation of sevelamer nanoparticles endows it have potential from 'bench to bedside' as a new type of vascular embolic.

Intratumoral Pi deprivation benefits chemoembolization therapy via increased accumulation of intracellular doxorubicin.

It is a decade-long controversy that transarterial chemoembolization (TACE) has definite priority over transarterial embolization (TAE) in treating patients with hepatocellular carcinoma (HCC), since HCC cells are regularly resistant to chemotherapy by enhanced expression of proteins that confer drug resistance, and ABC transporters pump the intracellular drug out of the cell. We addressed this issue by modulating the chemo-environment. In an animal model, sevelamer, a polymeric phosphate binder, was introduced as an embolic agent to induce intratumoral inorganic phosphate (Pi) starvation, and trans-arterially co-delivered with doxorubicin (DOX). The new type of TACE was named as DOX-TASE. This Pi-starved environment enhanced DOX tumoral accumulation and retention, and DOX-TASE thereby induced more severe tumor necrosis than that induced by conventional TACE (C-TACE) and drug-eluting bead TACE (D-TACE) at the same dose. In vitro tests showed that Pi starvation increased the cellular accumulation of DOX in an irreversible manner and enhanced cytotoxicity and cell apoptosis by suppressing the expression of ABC transporters (P-glycoprotein (P-gp), BCRP, and MRP1) and the production of intracellular ATP. Our results are indicative of an alternative interventional therapy combining chemotherapy with embolization more effectively.

Predictive value of T2-weighted imaging and dynamic contrast-enhanced MRI for assessing cervical invasion in patients with endometrial cancer: a meta-analysis.

PURPOSE: To obtain the diagnostic accuracy of T2-weighted imaging (T2WI), and dynamic contrast-enhanced MRI (DCE-MRI) in the preoperative assessment of cervical invasion in patients with endometrial cancer (EC). METHODS: Databases including PubMed, Embase, Cochrane Library, Web of Science, and Clinical Trials were searched for relevant articles published from January 2000 to August 2020. Pooled estimation data were obtained by statistical analysis. RESULTS: In total, 24 articles were included. For assessing cervical invasion of EC, the pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the curve (AUC) for T2WI were 0.70 (0.61-0.77), 0.92 (0.89-0.94), 8.7 (6.5-11.6), 0.33 (0.25-0.43), 26 (17-41), and 0.92 (0.89-0.94), respectively. For DCE-MRI, the pooled sensitivity, specificity, PLR, NLR, DOR, and AUC were 0.75 (0.60-0.85), 0.95 (0.89-0.98), 14.7 (6.6-32.9), 0.27 (0.16-0.44), 55 (18-165), and 0.92 (0.89-0.94), respectively; for T2WI combined with DCE-MRI, they were 0.58 (0.41-0.73), 0.98 (0.95-0.99), 28.1 (12.8-62.1), 0.43 (0.30-0.63), 65 (29-146), and 0.94 (0.91-0.96), respectively. CONCLUSIONS: DCE-MRI demonstrated higher diagnostic performance than T2WI in the prediction of cervical invasion in patients with EC. T2WI combined with DCE-MRI improved the pooled specificity, PLR, DOR, and AUC compared to T2WI alone or DCE-MRI alone.

Ultrasound-Guided Percutaneous Ethanol-Paclitaxel Combined Therapy for Rabbit VX2 Liver Tumors.

BACKGROUND: It is difficult to achieve whole tumor ablation using percutaneous ethanol ablation therapy (PEAT) due to the limited diffusion of ethanol. PURPOSE: To determine whether chemotherapy can be an adjuvant therapy to benefit PEAT, we investigated ultrasound-guided percutaneous ethanol-paclitaxel combined therapy (PEPCT) of VX2 carcinoma, a rabbit liver cancer model. MATERIALS AND METHODS: A six-arm study was designed to quantify the correlation between paclitaxel (PTX) dose and tumor necrosis or cell proliferation, including sham group (2 mL saline, n=6), incremented dose of PTX (0, 12.5, 25, 37.5 mg) in 2.0 mL ethanol (n=6) and a conventional PEAT group (n=6) as comparison. The test was followed by contrast-enhanced ultrasonic (CEUS) before 7-day sacrifice, tumor harvest, and sectioning. Tumor necrosis ratio was radiologically and histologically quantified; modified proliferation index (m-PI) was proposed to quantify the PTX's pharmacological effects. A linear regression model was set to correlate the PTX dose with tumor necrosis ratio or cell proliferation index. The difference of radiological, histological necrosis ratio (HNR) and modified PI in six groups was analyzed via Kruskal-Wallis H-test, Welch analysis of variance and one-way ANOVA. RESULTS: Incremental increases of PTX (0, 12.5, 25, 37.5 mg) correlated with greater fraction of tumor necrosis (R2 = 0.946, P<0.001 for radiological necrosis ratio [RNR], R2 = 0.843, P<0.001 forHNR), indicating that one week after procedure PTX's anti-proliferation and ethanol's dehydration co-induced severe tumor necrosis. Correlation analysis further testified a significant association between PTX dose and m-PI (R2 = 0.860, P<0.001). CONCLUSION: These results suggest a clear role for PTX-induced cytotoxicity and support the use of chemotherapeutic drugs in ablation therapy.

Exosomal connexin 43 regulates the resistance of glioma cells to temozolomide.

Glioblastoma is the most common and aggressive brain tumor and it is characterized by a high mortality rate. Temozolomide (TMZ) is an effective chemotherapy drug for glioblastoma, but the resistance to TMZ has come to represent a major clinical problem, and its underlying mechanism has yet to be elucidated. In the present study, the role of exosomal connexin 43 (Cx43) in the resistance of glioma cells to TMZ and cell migration was investigated. First, higher expression levels of Cx43 were detected in TMZ­resistant U251 (U251r) cells compared with those in TMZ­sensitive (U251s) cells. Exosomes from U251s or U251r cells (sExo and rExo, respectively) were isolated. It was found that the expression of Cx43 in rExo was notably higher compared with that in sExo, whereas treatment with rExo increased the expression of Cx43 in U251s cells. Additionally, exosomes stained with dioctadecyloxacarbocyanine (Dio) were used to visualized exosome uptake by glioma cells. It was observed that the uptake of Dio­stained rExo in U251s cells was more prominent compared with that of Dio­stained sExo, while 37,43Gap27, a gap junction mimetic peptide directed against Cx43, alleviated the rExo uptake by cells. Moreover, rExo increased the IC50 of U251s to TMZ, colony formation and Bcl­2 expression, but decreased Bax and cleaved caspase­3 expression in U251s cells. 37,43Gap27 efficiently inhibited these effects of rExo on U251s cells. Finally, the results of the wound healing and Transwell assays revealed that rExo significantly enhanced the migration of U251s cells, whereas 37,43Gap27 significantly attenuated rExo­induced cell migration. Taken together, these results indicate the crucial role of exosomal Cx43 in chemotherapy resistance and migration of glioma cells, and suggest that Cx43 may hold promise as a therapeutic target for glioblastoma in the future.

Diagnostic Accuracy of MRI for Detecting Cervical Invasion in Patients with Endometrial Carcinoma: A Meta-Analysis.

Objectives: To evaluate the diagnostic accuracy of magnetic resonance imaging (MRI) in the preoperative assessment of cervical invasion and to analyse the influence of different imaging protocols in patients with endometrial carcinoma. Methods: An extensive search of articles about MRI for assessing cervical invasion in patients with endometrial carcinoma was performed on PubMed, Embase, Web of Science, Cochrane Library, and Clinical Trials from January 2000 to July 2020. Two reviewers independently evaluated the methodological quality of each study by using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2). Diagnostic accuracy results and additional useful information were extracted. The pooled estimation data was obtained by statistical analysis. Results: A total of 42 eligible studies were included in the meta-analysis. Significant evidence of heterogeneity was found for detecting cervical invasion (I2 = 74.1%, P = 0.00 for sensitivity and I2 = 56.2%, P = 0.00 for specificity). The pooled sensitivity and specificity of MRI were 0.58 and 0.95 respectively. The use of higher field strength (3.0 T) demonstrated higher pooled sensitivity (0.74). Using diffusion weighted imaging (DWI) alone presented higher pooled sensitivity (0.86) than using other sequences. The studies that used dynamic contrast-enhanced MRI (DCE-MRI) alone showed higher sensitivity (0.80) and specificity (0.96) than those that used T2-weighted imaging (T2WI) alone. Conclusions: MRI shows high specificity for detecting cervical infiltration in endometrial carcinoma. Using DWI or a 3.0-T device may improve the pooled sensitivity. DCE-MRI demonstrates higher pooled sensitivity and specificity than T2WI.

The value of clinical parameters combined with magnetic resonance imaging (MRI) features for preoperatively distinguishing different subtypes of uterine sarcomas: An observational study (STROBE compliant).

To investigate clinical parameters combined with magnetic resonance imaging (MRI) features including apparent diffusion coefficient (ADC) values in preoperative identification of different subtypes of uterine sarcomas including uterine leiomyosarcoma (LMS), endometrial stromal sarcoma (ESS), and carcinosarcoma (CS).Data from 71 patients with uterine sarcoma confirmed by surgery and pathology were collected. The clinical characteristics, conventional MRI features, mean ADC values, minimum ADC values, and lesion-muscle ADC ratio (rADC) values were compared with different subtypes of uterine sarcomas.Age, clinical manifestation, tumor location, shape, and T1-weighted image (T1WI) signals were significantly different between CS and LMS or ESS (all P < .01). The presence of band sign was significantly higher in ESS than in LMS or CS (both P < .001). The cystic change or necrosis and enhancement could help to differentiate LMS from ESS or CS (both P < .02). Significant differences were observed in T2-weighted image (T2WI) signals of the solid components of LMS compared with CS (P < .001). There was a significant difference between ESS and CS in the rADC values (P = .004).Clinical parameters combined with MRI features could help narrowing preoperative diagnostic possibilities in distinguishing subtypes of uterine sarcomas. These findings may be beneficial in helping guide operative decisions.

Adverse outcomes of proton pump inhibitors in chronic liver disease: a systematic review and meta-analysis.

BACKGROUND AND AIM: Proton pump inhibitors (PPIs) are among the most commonly prescribed medications in the US, but their safety in cirrhosis has recently been questioned. We performed a meta-analysis of observational studies to evaluate the impact of PPIs on adverse clinical outcomes in the setting of chronic liver disease (CLD). METHODS: We searched several databases from inception to 26 May 2019 to identify comparative studies evaluating the effect of PPIs in CLD. Outcomes of interest were the associations between PPIs use and the occurrence of hepatic encephalopathy, hepatocellular carcinoma, spontaneous bacterial peritonitis, bacterial infections, and mortality in CLD. We performed a meta-analysis in accordance to the PRISMA guidelines. RESULTS: Of 14,662 papers evaluated, 47 studies with 169,806 participants were identified. Of these, 35 were cohort studies and 12 were case-control studies. The pooled odds ratio (OR) for hepatic encephalopathy in individuals with PPI users, compared with those without, was 2.31 (95% CI 1.63-3.28). The pooled OR for spontaneous bacterial peritonitis in individuals with PPI users was significantly higher compared with non-PPI users (OR = 1.72, 95% CI 1.42-2.09). Results were also consistent with a higher risk of the bacterial infections and mortality in PPI users compared with non-PPI users. For hepatocellular carcinoma, the final conclusion cannot be drawn because of the limited number of studies. CONCLUSIONS: This study identifies a significant relationship between PPIs therapies and several specific adverse clinical outcomes in CLD. However, these results should be carefully considered given the potential selection bias and unmeasured confounding variables in observational studies, it may be reasonable to re-evaluate the need for PPIs in patients with CLD.